Breast cancer is the most frequently diagnosed cancer in women; 1 in 8 women in the United States will be diagnosed with this disease during their lifetime. Advances in detection and treatment have substantially increased the 5-year survival rate for breast cancer patients. However, among this population of survivors, the incidences of depression and anxiety are approximately 3-5 times higher than among women in the general population. Despite this striking increase, the etiology of depression and anxiety among breast cancer patients remains unknown. In mice, we have been able to establish a causal link between chemotherapy-induced neuroinflammation and changes in affective behavior. The first goal of this proposal is to determine whether having a tumor that has been resected primes the inflammatory response to chemotherapy and to determine how neuroinflammation and affective behavior change over the course of multiple chemotherapy treatments. The second goal of this proposal is to determine whether factors that are hypothesized to contribute to individual differences in susceptibility to the development of depression and anxiety after chemotherapy, specifically stress and social isolation, do so by increasing the proinflammatory consequences of chemotherapy. Our preliminary data indicate that stress exposure and social isolation significantly increase depressive-like behavior and anxiety-like behavior, respectively, among mice treated with chemotherapy. The experiments in Aim 2 will determine whether the chemotherapy-induced exacerbation of depressive-like behavior is achieved through a mechanism involving corticosteroid mediated increases in neuroinflammation, and whether blocking the glucocorticoid response to stress reduces the neuroinflammatory and affective consequences of chemotherapy. The experiments in Aim 3 will determine whether affiliative social interaction provides a buffer against chemotherapy-induced neuroinflammation, and affective changes. The proposed research represents the first experimental test of the hypothesis that modulation of chemotherapy-induced neuroinflammation alters the risk of developing depression and anxiety. The long-range goal of the proposed research is to improve the mental and physical health of cancer patients, as well as their quality of life, through the alleviation of depression and anxiety. The important first stp in achieving this goal is improved understanding of the biological processes through which environmental factors influence susceptibility to chemotherapy-related affective disorders.